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SGLT-2 Inhibitors: An Evidence-Based Practice Approach DAP14004.1045 Revised Draft for ResubmissionJanuary 7, 2016

Sodium-Glucose Cotransporter-2 Inhibitors: An Evidence-Based Practice Approach to

Their Use in the Natural History of Type 2 Diabetes

1

Document Type:Review Revised Draft for Resubmission

Authors:Stanley S. Schwartz, MDIntekhab Ahmed, MD

Target Publication:Current Medical Research and Opinion

Editorial Support:Scarlett Geunes-Boyer, PhDJanet Matsuura, PhD

Draft and date:Revised Draft for Resubmission January 7, 2016

CHC Project NumberDAP14004.1045

One Dickinson DriveSuite 200Chadds Ford, PA 19317-9665Phone (610) 358-3600Fax (610) 358-3636


Sodium-Glucose Cotransporter-2 Inhibitors: An Evidence-Based Practice Approach to

Their Use in the Natural History of Type 2 Diabetes

Short title: SGLT-2 Inhibitor Therapy in Type 2 Diabetes

Stanley S. Schwartz, MD1 and Intekhab Ahmed, MD2

1Main Line Health System, Ardmore, PA; 2Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA

Article type: Review

Corresponding author and reprint requests:

Stanley S. Schwartz, MD

Emeritus, Clinical Associate Professor of Medicine,

University of Pennsylvania

Affiliate, Main Line Health System

Ardmore, PA 19003

Phone: 610-642-6800

Fax: 610-642-6850

Email: [email protected]

Co-authorIntekhab Ahmed, MDThomas Jefferson University 2301 S. Broad Street, Suite 106Philadelphia, PA 19148Email: [email protected]

2

mailto:[email protected]


Abstract

Objective: The sodium-glucose cotransporter-2 (SGLT-2) inhibitors are an important addition to

available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet

and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients

receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or

insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for

approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers

blood glucose concentrations. The objective of this review is to discuss the pathophysiology of

diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-

based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D.

Methods: PubMed and Google Scholar databases were searched to identify literature published

from 1990 through September 2015 examining the pathophysiology of T2D, the role of the

kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of

SGLT-2 inhibitors in T2D.

Results: There is a need for early treatment in patients with T2D to minimize the risk of

cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve

glycemic control, reduce body weight and blood pressure, and are associated with a low risk of

hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate

urinary tract and genital infections and mild dehydration potentially leading to orthostatic

hypotension.

Conclusions: An evidence-based practice approach to examining the importance of early,

proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to

increasingly more complicated combination therapy regimens, including insulin, suggests that

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this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2

inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of

clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.

Key words: sodium-glucose cotransporter-2 inhibitor, type 2 diabetes, evidence-based practice

approach, canagliflozin, dapagliflozin, and empagliflozin

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Introduction

The prevalence of type 2 diabetes (T2D) is increasing coincident with the rising obesity

epidemic1,2. Based on the 2011 to 2012 National Health and Nutrition Examination Survey, an

estimated 12.3% to 14.3% of adults in the United States have diabetes and an additional 38%

have prediabetes3, a condition that substantially increases the risk of developing both T2D, with

an estimated lifetime risk at age 45 years of 74%4, as well as cardiovascular disease5. Other risk

factors for T2D include age, obesity, physical inactivity, hypertension, dyslipidemia, ethnicity,

and some medications, such as glucocorticoids6. Although still uncommon, the prevalence of

T2D among adolescents is increasing7 and is predicted to further increase by 50% or more by

20508. With an earlier onset and longer disease duration, which can increase the risk for

microvascular and macrovascular changes, including myocardial damage and atherosclerosis9-11,

this increased prevalence could have profound consequences on productivity, quality of life, and

health care costs8. In fact, many patients present with diabetes-related complications at the time

of T2D diagnosis12, suggesting the presence of tissue damage associated with hyperglycemia

before the presentation of diagnostic clinical signs and symptoms13.

Management of hyperglycemia in patients with T2D has evolved from administration of drugs

targeted to the pancreas to stimulate glucose-independent insulin secretion to an increasing

armamentarium of drug classes with mechanisms that address different factors contributing to or

resulting from the β-cell dysfunction underlying the development and progression of T2D

(Figure 1)14-16. Thus, the principle underlying effective treatment should be to use the fewest

agents to affect the greatest number of target mechanisms in a patient-tailored manner.

5


By promoting weight loss and reducing glucose toxicity to the β cell17,18, sodium-glucose

cotransporter-2 (SGLT-2) inhibitors affect several of these mechanisms. These agents lower

blood glucose concentrations by inhibiting SGLT-2 in the proximal renal tubule, diminishing

reabsorption of glucose and facilitating its excretion in the urine17. As an adjunct to dietary

modifications and exercise, SGLT-2 inhibitors may be prescribed alone or in combination with

metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4)

inhibitors, or insulin19-21. Members of this class currently approved in the United States are

canagliflozin, dapagliflozin, and empagliflozin.

The aim of this review is to provide an evidence-based practice approach, defined as An

evidence-based approach to clinical practice reflects an integration of the best external clinical

data, clinician expertise, and patient perspectives into treatment decisions22,23 ., to clinical

applications of SGLT-2 inhibitors in the treatment of T2D. This review encompasses the stages

of T2D development, the renal contribution to glucose homeostasis and pathophysiology of T2D,

and disease treatment from initiation of pharmacotherapy to increasingly more complicated

combination therapy regimens that may include insulin, in which SGLT-2 inhibitors have been

shown to provide beneficial effects.

Methods

An evidence-based approach to clinical practice reflects an integration of the best external

clinical data, clinician expertise, and patient perspectives into treatment decisions22,23. PubMed

and Google Scholar databases were searched to identify literature published from 1990 through

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September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating

glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in

T2D. The search terms included type 2 diabetes, SGLT-2 inhibitor, dapagliflozin, canagliflozin,

and empagliflozin. The information from the published literature was supplemented by the

clinical experience of the authors.

Natural History of Type 2 Diabetes and the Role of Sodium-Glucose Cotransporter-2

Inhibitors

In healthy individuals, insulin secretion following a meal suppresses glucose production in the

liver and stimulates the uptake of glucose, amino acids, and fatty acids from the bloodstream into

muscle and adipose tissue. In early stages of disease, peripheral tissue responsiveness to

circulating insulin is reduced, and pancreatic β cells increase insulin secretion to compensate for

this insulin resistance. Over time, the ability of pancreatic β cells to release sufficient insulin to

compensate for the rising glycemia declines, resulting in the impaired fasting glucose and/or

impaired glucose tolerance associated with prediabetes. Further disease progression is

characterized by continued β-cell deterioration and chronically elevated blood glucose

concentrations24. The sustained hyperglycemia associated with prediabetes and T2D has been

associated with glucotoxicity, accelerated lipolysis of fat cells, diminished response to incretin

hormones, pancreatic α -cell–generated hyperglucagonemia, increased glucose reabsorption in

the kidney, and insulin resistance in the brain13,24. Thus, hyperglycemia is not only a marker of

T2D but a pathogenic factor that contributes to disease progression and the development of

diabetes-related complications. Because the mechanisms underlying the development of T2D are

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initiated before or during prediabetes, early implementation of treatments to reduce or prevent

further increases in glucose concentrations may slow disease progression and minimize the risk

of developing long-term, life-threatening microvascular and macrovascular complications

(Figure 2)25-27.

The kidney filters and returns glucose back into the bloodstream to maintain physiologic glucose

concentrations, and approximately 90% of glucose reabsorption occurs via SGLT-2 in the

proximal renal tubule28,29. SGLT-2 protein expression and activity is upregulated in patients with

T2D, postulated teleologically as an adaptive response to a perceived loss of glucose, to maintain

glucose concentrations for normal brain function30. The renal threshold and reabsorptive capacity

for glucose is increased in T2D, such that glucose excretion in the urine occurs only at higher

plasma glucose concentrations, perpetuating hyperglycemia31. SGLT-2 inhibitors reduce glucose

reuptake by inhibiting SGLT-2 transport, resulting in the excretion of excess glucose in the urine

(glucosuria)13,17,28. Mixed effects of SGLT-2 inhibitors on renal function have been reported. In

clinical trials, early reductions in eGFR that stabilize with continued treatment have been noted,

as have reductions in albuminuria32-34. Preliminary findings suggest that SGLT-2 inhibitors may

provide beneficial intrarenal effects in patients with T2D, as evidenced by decreases in

hyperfiltration, glomerular hypertension, and albuminuria and maintenance of stable renal

function35.

Furthermore, SGLT-2 inhibitors suppress the glomerular hyperfiltration associated with

diabetes36,37, which has been suggested to be a risk factor for progression to chronic kidney

disease36. Thus, SGLT-2 inhibitors have the potential to slow or prevent declines in renal

function in patients with diabetes36. Renal excretion of glucose depends both on the plasma

8


concentration of glucose and the glomerular filtration rate (GFR); thus, for patients with similar

plasma glucose concentrations, the efficacy of SGLT-2 inhibitors is expected to be diminished

in those patients with a lower GFR. As a result of the likelyis decrease ind efficacy and because

ofin addition to safety concerns related to impaired autoregulation of renal blood flow in patients

with moderate to severe renal impairment38, the SGLT-2 inhibitors are not indicated in patients

with an estimated GFR (eGFR) below specified limits (dapagliflozin, eGFR <60 mL/min/1.73

m2; canagliflozin and empagliflozin, eGFR <45 mL/min/1.73 m2) 19-21.

The decline in β-cell function underlies the progression from normal glycemic concentrations to

T2D15,16. The SGLT-2 inhibitors provide a therapeutic option for T2D that, like metformin and

TZDs, reduce A1C independently of the function of β cells and, by reducing glucotoxicity,

potentially preserve β-cell viability. Their additional beneficial weight and blood pressure-

reducing effects of the SGLT-2 inhibitors position them as a potentially viable treatment option

throughout all stages of the natural history of T2D, with their selection based on a careful

assessment of the medical history, comorbid conditions, and requirements of each patient.

Glycemic Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors

The glycemic efficacy of SGLT-2 inhibitors as monotherapy in drug-naïve patients and as

combination therapy with other antidiabetes agents has been evaluated in clinical trials and in a

45-trial meta-analysis (Table 1)39.

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Canagliflozin (100 and 300 mg) reduced glycated hemoglobin (A1C) compared with placebo as

monotherapy (–0.91% to –1.03% and –1.16%, respectively)40,41 and as add-on therapy to

metformin, metformin plus SU, metformin plus pioglitazone, or insulin (–0.62% to –0.71% and –

0.76% to –0.92%, respectively)42-45. In patients on background metformin, canagliflozin 100 and

300 mg were noninferior to glimepiride in lowering A1C at 52 weeks (–0.82% and –0.93%,

respectively, vs –0.81% for glimepiride)46, and this effect was sustained for 2 years47. Similarly,

in patients receiving metformin plus SU, canagliflozin 300 mg was noninferior to sitagliptin in

lowering A1C at 52 weeks (–1.03% for canagliflozin 300 mg vs –0.66% for sitagliptin)48.

Dapagliflozin 5 and 10 mg as monotherapy produced placebo-adjusted A1C reductions ranging

from –0.35% to –0.84% and from –0.39% to –0.82%, respectively49-52. In patients with T2D

inadequately controlled with metformin, glimepiride, sitagliptin ± metformin, pioglitazone, or

insulin plus up to 2 oral antidiabetes agents, dapagliflozin provided significant reductions in A1C

at 24 weeks (P <0.001)53-57, and this effect was maintained for up to 4 years in patients with T2D

uncontrolled with metformin or insulin54,58,59. In treatment-naïve patients with T2D, the

combination of dapagliflozin (5 or 10 mg) and metformin extended release significantly reduced

A1C compared with either treatment alone (P<0.0001)60. In patients with T2D uncontrolled with

metformin, add-on dapagliflozin or glipizide produced identical reductions in A1C (–0.52%)61.

In a trial comparing dual add-on dapagliflozin 10 mg plus saxagliptin 5 mg to metformin with

single add-on of either drug, A1C reductions were –1.47% with dual add-on, 0.88% with

saxagliptin add-on, and 1.2% with dapagliflozin add-on62.

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Empagliflozin 10 and 25 mg as monotherapy reduced A1C by –0.74% to –0.86%, respectively,

versus placebo63. As add-on with metformin, metformin plus SU, and pioglitazone ± metformin,

placebo-adjusted A1C reductions for empagliflozin 10 and 25 mg ranged from –0.48% to –

0.65% and from –0.60% to –0.64%, respectively64-67. Empagliflozin 10 or 25 mg with linagliptin

5 mg as initial combination or dual add-on to metformin therapy reduced A1C by –1.24% and –

1.08% and by –1.08% and –1.19%, respectively68,69.

Moreover, SGLT-2 inhibitors reduced both fasting and postprandial glucose

concentrations40,41,44,45,47-49,55-57,61,63-67,70, which can increase the duration of normoglycemia71.

Additional Actions and Effects of Sodium-Glucose Cotransporter-2 Inhibitors

In contrast to manysome commonly used glucose-lowering drugs, insulin, SUs, and TZDs, which

are associated with weight gain, metformin, glucagon-like peptide-1 receptor agonists,

pramlintide, and SGLT-2 inhibitors are associated with decreases in weight72. Weight reductions

associated with SGLT-2 inhibitors are shown in , the SGLT-2 inhibitors are associated with

decreases in weight (Table 1). In patients with T2D on background metformin, canagliflozin 100

and 300 mg produced weight reductions compared with weight gain with glimepiride at 52

weeks (–3.7 and –4.0 kg for canagliflozin 100 and 300 mg, respectively, vs +0.7 kg for

glimepiride; P <0.001), which persisted for up to 104 weeks46. Canagliflozin 100 and 300 mg

also provided dose-dependent weight reductions after 26 weeks compared with placebo in

patients with T2D inadequately controlled with metformin plus an SU (–1.9 and –2.5 kg,

respectively, vs –0.8 kg for placebo; P <0.001)45. In patients with T2D inadequately controlled

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with metformin receiving ≤10 mg/day dapagliflozin or ≤20 mg/day glipizide, mean weight

changes after 52 weeks of treatment were –3.2 and +1.4 kg (P <0.001), respectively61. Studies of

patients with T2D not controlled on metformin, glimepiride, sitagliptin ± metformin, or insulin ±

up to 2 antidiabetes agents also demonstrated weight reductions with add-on dapagliflozin 10

mg53-55,57. Weight decreases with dapagliflozin were generally maintained over time, and in 1

study were maintained for up to 4 years59. Empagliflozin at doses of 10 and 25 mg as

monotherapy or combination therapy provided weight reductions ranging from –1.5 to –3.0 kg

after 24 weeks in patients with T2D (P <0.001; Table 1)65-69. SGLT-2 inhibitor−induced weight

loss has been associated with a reduction of fat mass as opposed to lean tissue18,46,73.

Sodium-glucose cotransporter-2 inhibitors have been associated with decreases in blood

pressure, particularly systolic blood pressure (SBP), likely resulting, at least in part, from the

mild diuretic effects of these agents74. In double-blind controlled trials of 24 to 26 weeks,

canagliflozin, dapagliflozin, and empagliflozin reduced SBP by 2 to 5 mmHg compared with

placebo41-43,45,52,53,55-57,63,65-67.

Mixed effects of SGLT-2 inhibitors on renal function have been reported. In clinical trials, early

reductions in eGFR that stabilize with continued treatment have been noted, as have reductions

in albuminuria71-73. Preliminary findings suggest that SGLT-2 inhibitors may provide beneficial

intrarenal effects in patients with T2D, as evidenced by decreases in hyperfiltration, glomerular

hypertension, and albuminuria and maintenance of stable renal function74.

Tolerability and Adverse Events

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Sodium-glucose cotransporter-2 inhibitors have a generally favorable safety profile in patients

with T2D, with a low propensity to cause hypoglycemia when used as monotherapy or in

combination with metformin, TZDs, and DPP-4 inhibitors (Table 2). Episodes of hypoglycemia

were mostly mild and reported in 0 to 7% of patients, and major hypoglycemia, defined as an

event requiring third-party assistance, was uncommon (Table 2). An increased risk of

hypoglycemia was observed when an SGLT-2 inhibitor was administered with insulin or an

SU44,45,54,57,67,75,76. However, studies comparing an SGLT-2 inhibitor versus an SU as add-on

therapy to metformin have demonstrated similar efficacy but a 5- to 10-fold reduced incidence

of hypoglycemia with the SGLT-2 inhibitor (3.4%–6% vs 25%–39.7%, respectively)46,61,64.

Consequently, SGLT-2 inhibitors have been suggested as an alternative to SUs, which pose risks

of hypoglycemia, weight gain, and β-cell apoptosis6,77.

Urinary tract and genital infections have been reported with SGLT-2 inhibitor use (Table 2). A

meta-analysis of 45 randomized controlled trials comparing an SGLT-2 inhibitor with placebo or

another antidiabetes agent in patients with T2D showed an increased incidence of urinary tract

infections (placebo: odds ratio [OR], 1.34 [CI, 1.03–1.74]; other agent: OR, 1.42 [CI, 1.06–

1.90]) and genital infections (placebo: OR, 3.50 [CI, 2.46 – 4.99]; other agent: OR, 5.06 [CI,

3.44 – 7.45])39. These infections were typically mild or moderate, responded to standard

treatment, and did not result in study discontinuations78-81.

The diuretic effects of SGLT-2 inhibitors may increase urine frequency and volume (up to 400

mL/24 hours), potentially leading to orthostatic hypotension, slight increases in hematocrit, and

13


small decreases in serum uric acid but no significant changes in plasma electrolyte

concentrations57,61,62,82-84. No changes or slight reductions in triglycerides and modest increases in

high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol concentrations

have been noted with SGLT-2 inhibitors, without significant changes in HDL:LDL ratios40,53,64,65.

A recentA US Food and Drug Administration (FDA) warning safety reviews have resulted in the

addition of warnings to the prescribing information for SGLT-2 inhibitors regarding the risks of

reported 20 cases of diabetic ketoacidosis associated with SGLT-2 inhibitors from March 2013

to June 2014and of serious urinary tract infection85,86. Both conditions can lead to

hospitalization.; the The FDA is released a report regarding the risk of ketoacidosis with SGLT-2

inhibitor use in May 2015continuing to monitor this issue. The FDA Adverse Event Reporting

System (FAERS) database was reviewed from March 2013 to May 2015, and 73 cases of

ketoacidosis were identified in patients with T1D or T2D receiving SGLT2 inhibitors. The

European Medicines Agency is also monitoring diabetic ketoacidosis risk with SGLT-2

inhibitors following reports of 101 cases worldwide among patients receiving SGLT-2

inhibitors87. Increased glucagon88, which has ketogenic properties, and decreased ketone body

clearance have been postulated as potential underlying mechanisms89.

Urosepsis and kidney infections (pyelonephritis) that developed from urinary tract infections in

19 patients using SGLT2 inhibitors were reported to FAERS from March 2013 through October

2014. All patients were hospitalized, and a few were admitted to an intensive care unit or

underwent dialysis for the treatment of kidney failure85.

14


An imbalance in newly diagnosed bladder cancer with dapagliflozin (0.17%) versus comparator

(0.03%) across dapagliflozin clinical studies was previously noted; however, only 4 of 11 cases

occurred after 1 year of exposure, limiting determination of causality. Dapagliflozin is not

recommended for patients with bladder cancer and should be used with caution in patients with a

history of bladder cancer20.

The FDA has recently reinforced an earlier warning of an increased risk of bone fractures and

added new information concerning decreases in bone mineral density with canagliflozin to the

drug label based on data pooled from clinical trials and an FDA-requested postmarketing study

assessing bone mineral density in older patients with T2D90.

Clinical Practice Experience

The SGLT-2 inhibitors reduce blood glucose concentrations, which may decrease glucose

toxicity to β cells and thus improve β-cell function91-93, and reduce body weight and SBP. SGLT-

2 inhibitors also have a relatively fast onset of action, which may improve patient adherence. Thus,

for patients early in the disease, we have found that SGLT-2 inhibitors can be incorporated into

therapeutic regimens combining appropriate agents for effective control of hyperglycemia while

minimizing hypoglycemia, weight gain, and β-cell apoptosis. For patients with more progressive

disease, incorporation of SGLT-2 inhibitors can often delay initiation of insulin, facilitate insulin

dose reduction, or, in some cases, allow for the discontinuation of insulin or insulin

secretagogues, which are associated with a risk of hypoglycemia, weight gain, or other adverse

events94.

15


The SBP reduction and mild dehydration associated with the diuretic effects of SGLT-2

inhibitors can cause lightheadedness, dizziness, and, rarely, nausea in some patients. Thus, we

advise treated patients to maintain proper hydration. In patients with low blood pressure

initiating SGLT-2 inhibitor therapy, clinicians should consider proactively reducing the dose of

or discontinuing concomitant antihypertensive or diuretic treatment. Concerns regarding the

reversal of microalbuminuria reductions by discontinuing angiotensin-converting enzyme

inhibitor/angiotensin receptor blocker therapy may be offset by findings that SGLT-2 inhibitors

also reduce albuminuria32-34.

Although SGLT-2 inhibitors are associated with Despite an increased risk of urinary tract and

genital infections with SGLT-2 inhibitors, these infections are typically amenable to treatment

with standard courses of antibiotics for urinary tract infections and over-the-counter antifungal

creams or prescription fluconazole 150 mg/d taken once upon receipt and once 2 days later for

genital infections. The the occurrence of urosepsis or pyelonephritis was is rare80,95, but patients

should be monitored given the recent FDA warning of serious urinary tract infections85.. In

practice, wWe have successfully minimized the former risks by advising patients to consume

large fluid volumes and practice fastidious bathroom habits; but however, based on the available

evidence, we do not recommend SGLT-2 inhibitors in patients with a history of frequent urinary

tract or yeast infections.

It has been suggested that the potential risk of diabetic ketoacidosis in patients treated with

SGLT-2 inhibitors may be diminished by combining an SGLT-2 inhibitor with a DPP-4 inhibitor

16

Geunes-Boyer, Scarlett, 01/05/16,

Dr. Schwartz: Please provide details regarding standard treatment for UTIs.


or glucagon-like peptide-1 receptor agonist, which possess additive glycemic and weight

benefits96, as a logical preventive approach to this potential side effect because of their. capacity

to reduce glucagon97.

Concerns that long-term glucosuria with SGLT-2 inhibitor use could lead to kidney damage may

be somewhat alleviated by the lack of severe adverse outcomes, such as kidney damage and early

mortality, in patients with familial renal glucosuria resulting from mutations in the SLC5A2 gene

for SGLT-298,99. In addition, SGLT-2 inhibitors have been shown to reverse glomerular

hyperfiltration, a potential early indicator of kidney disease36. Also encouraging are results of the

recently published EMPA-REG OUTCOME trial conducted in 7020 patients with T2D and

established cardiovascular disease, in which a significantly lower proportion of patients treated

with empagliflozin versus placebo experienced the primary composite end point of death from

cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (10.5% vs 12.1%;

P=0.04 for superiority), or individual outcomes of death from any cause (P<0.001), death from

cardiovascular causes (P<0.001), or hospitalization for heart failure (P=0.002)100. Despite these

encouraging results, it most be noted that the composite end point of EMPA-REG was driven by

a significant decrease in death from cardiovascular causes in high-risk patients receiving

empagliflozin versus placebo. The risk of myocardial infarction or stroke did not differ between

the treatment groups, with a small numeric increase in stroke observed with empagliflozin100.

Thus, we conclude that empagliflozin is an appropriate drug choice for the treatment of high-risk

patients with T2D who have previously had a myocardial infarction, and although it is likely to

benefit a broader group of patients, additional conclusive data are needed. F urthermore,

whetherIt is not known if thisa potential cardiovascular benefit extends to other members of the

17


SGLT-2 inhibitor class is not known, for whichand CCardiovascular outcomes trials for

canagliflozin and dapagliflozin are currently underway101,102 and should provide a more definitive

answer as to whether a potential cardiovascular benefit extends to other members of the SGLT-2

inhibitor class. Findings from In a post hoc analysis of 21 phase 2b/3 trials in patients with T2D,

showed that dapagliflozin was not associated with an increased cardiovascular risk in high-risk

patients aged ≥65 years with a history of cardiovascular disease and hypertension103. A meta-

analysis of 9 phase 2 and 3 trials including interim data from the CANagliflozin cardioVascular

Assessment Study (CANVAS; 44% of patients; 80% of events), showed a lower occurrence of

major cardiovascular events, ie, death from cardiovascular causes, nonfatal myocardial

infarction, nonfatal stroke, or hospitalization due to unstable angina, with canagliflozin versus

comparator (18.9 vs 20.5 events per 1000 patient-years, hazard ratio [95% CI] = 0.91 [0.68,

1.21] )104. An early numeric increase in major cardiovascular events was observed that did not

extend past 30 days of treatment; however, it was not possible to determine whether this was a

chance finding or related to a mechanism underlying the treatment, such as volume depletion. A

numeric, but not statistically significant, increase in the occurrence of stroke was observed with

canagliflozin versus comparator (6.8 vs 4.6 events per 1000 patient-years, hazard ratio [95% CI]

= 1.46 [0.83, 2.58] in this preliminary analysis.

Collectively, these findings indicate that SGLT-2 inhibitors provide beneficial reductions in

blood glucose, weight, blood pressure, microalbuminuria, intrarenal inflammation, and

glomerular hyperfiltration, and they suggest thatsupport a cautiously optimistic outlook on the

long-term effects of SGLT-2 inhibitors; however, more longer duration trials are needed to

18


conclusively evaluate the durability of this drug class. are unlikely to pose a risk of long-term

negative effects and

Conclusion

Patients with T2D require early treatment to minimize the risk of developing cardiovascular

complications that increase morbidity and mortality. The SGLT-2 inhibitors improve glycemic

control by reducing glucose reabsorption and thus facilitating its excretion by the kidney. SGLT-

2 inhibitors may be prescribed alone or as add-on therapy in patients with inadequate glycemic

control with other agents. SGLT-2 inhibitors demonstrate beneficial effects on A1C, body

weight, and blood pressure, and have a low intrinsic propensity to cause hypoglycemia. Adverse

events include an increased risk of typically mild to moderate urinary tract and genital

infections; however, such risks can be mitigated by standard, logical clinical advice.

Thus, SGLT-2 inhibitors supplement the existing armamentarium of antidiabetes drugs,

affording physicians a larger arsenal with which to treat patients on an individualized basis to

achieve treatment goals.

19


Transparency

Declaration of funding AstraZeneca funded medical writing support for the preparation of this

manuscript, and agents of the sponsors reviewed the manuscript. All authors contributed to and

approved this manuscript.

Declaration of financial/other relationships

S. S. has served as an advisory board member for Janssen, Merck, AstraZeneca, Bristol-Myers

Squibb, Boehringer Ingelheim, Eli Lilly, Salix, Novo Nordisk, Takeda, and Genesis

Biotechnology Group and on the speaker’s bureaus of Takeda, Janssen, Merck, Novo Nordisk,

Salix, Boehringer Ingelheim, Eli Lilly, Eisai, AstraZeneca, Glaxo SmithKline, and Amgen.

I. A. reports no conflicts of interest.

Acknowledgements

Editorial support was provided by Scarlett Geunes-Boyer, PhD, and Janet E. Matsuura, PhD, of

Complete Healthcare Communications, LLC, and was funded by AstraZeneca.

20


References

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report:

Estimates of Diabetes and its Burden in the United States, 2014. 2014. Available at:

http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf [Last

accessed September 23, 2015]

2. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in

the United States, 2011-2012. JAMA 2014;311:806-14

3. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among

adults in the United States, 1988-2012. JAMA 2015;314:1021-9

4. Ligthart S, van Herpt TT, Leening MJ, et al. Lifetime risk of developing impaired

glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a

prospective cohort study. Lancet Diabetes Endocrinol 2015;

5. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014:

data sources, methods, and references for estimates of diabetes and its burden in the

United States. 2014. Available at: http://www.cdc.gov/diabetes/pdfs/data/2014-report-

national-diabetes-statistics-report-data-sources.pdf [Last accessed July 24, 2015]

6. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes

Care 2015;38:S88-S9

7. Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 2 diabetes

among children and adolescents from 2001 to 2009. JAMA 2014;311:1778-86

8. Imperatore G, Boyle JP, Thompson TJ, et al. Projections of type 1 and type 2 diabetes

burden in the U.S. population aged <20 years through 2050: dynamic modeling of

incidence, mortality, and population growth. Diabetes Care 2012;35:2515-20

21

http://www.cdc.gov/diabetes/pdfs/data/2014-report-national-diabetes-statistics-report-data-sources.pdf

http://www.cdc.gov/diabetes/pdfs/data/2014-report-national-diabetes-statistics-report-data-sources.pdf

http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf


9. Buysschaert M, Medina JL, Bergman M, et al. Prediabetes and associated disorders.

Endocrine 2015;48:371-93

10. Laakso M, Barrett-Connor E. Asymptomatic hyperglycemia is associated with lipid and

lipoprotein changes favoring atherosclerosis. Arteriosclerosis 1989;9:665-72

11. Selvin E, Lazo M, Chen Y, et al. Diabetes mellitus, prediabetes, and incidence of

subclinical myocardial damage. Circulation 2014;130:1374-82

12. UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic

patients and their association with different clinical and biochemical risk factors.

Diabetes Res 1990;13:1-11

13. DeFronzo R. From the triumvirate to the ominous octet: a new paradigm for the treatment

of type 2 diabetes mellitus. Diabetes 2009;58:773-95

14. Luck H, Tsai S, Chung J, et al. Regulation of obesity-related insulin resistance with gut

anti-inflammatory agents. Cell Metab 2015;21:527-42

15. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes:

perspectives on the past, present, and future. Lancet 2014;383:1068-83

16. Schwartz S, Epstein S, Corkey B, Grant S. The Time is Right for New Classification

System for Diabetes Mellitus: Rationale and Implications of the β-Cell Centric

Classification Schema. Diabetes Care [in press]

17. Jabbour SA, Whaley JM, Tirmenstein M, et al. Targeting renal glucose reabsorption for

the treatment of type 2 diabetes mellitus using the SGLT2 inhibitor dapagliflozin.

Postgrad Med 2012;124:62-73

18. Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total

fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus

22


with inadequate glycemic control on metformin. J Clin Endocrinol Metab 2012;97:1020-

31

19. Jardiance® (empagliflozin). Full Prescribing Information, Boehringer Ingelheim

Pharmaceuticals and Eli Lilly and Company, Ingelheim, Germany and Indianapolis, IN,

USA, 2014

20. Farxiga® (dapagliflozin). Full Prescribing Information, AstraZeneca, Wilmington, DE,

2015

21. Matthaei S, Rohwedder K, Grohl A, Johnsson E. Dapagliflozin improves glycaemic

control and reduces body weight as add-on therapy to metformin plus sulphonylurea.

European Association for the Study of Diabetes; 2013 September 23-27; Barcelona,

Spain

22. Duggal R, Menkes DB. Evidence-based medicine in practice. Int J Clin Pract

2011;65:639-44

23. Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based medicine: what it is and

what it isn't. BMJ 1996;312:71-2

24. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes

Care 2009;32:S151-6

25. UKPDS 33. Intensive blood-glucose control with sulphonylureas or insulin compared

with conventional treatment and risk of complications in patients with type 2 diabetes

(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53

26. UKPDS 34. Effect of intensive blood-glucose control with metformin on complications

in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study

(UKPDS) Group. Lancet 1998;352:854-65

23


27. Ramlo-Halsted BA, Edelman SV. The natural history of type 2 diabetes. Implications for

clinical practice. Prim Care 1999;26:771-89

28. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis:

a new path towards normalizing glycaemia. Diabetes Obes Metab 2012;14:5-14

29. Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel

strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract

2008;14:782-90

30. Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal

proximal tubular cells isolated from the urine of patients with non-insulin-dependent

diabetes. Diabetes 2005;54:3427-34

31. DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose

reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2

diabetes. Diabetes Care 2013;36:3169-76

32. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with

type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463-73

33. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2

diabetes and moderate renal impairment shows that dapagliflozin reduces weight and

blood pressure but does not improve glycemic control. Kidney Int 2014;85:962-71

34. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to

existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney

disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol

2014;2:369-84

24


35. Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for

renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens 2015;24:96-

103

36. De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotransporter 2 inhibitors

and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J

Kidney Dis 2014;64:16-24

37. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-

glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation

2014;129:587-97

38. Thomas MC. Renal effects of dapagliflozin in patients with type 2 diabetes. Ther Adv

Endocrinol Metab 2014;5:53-61

39. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2

inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med

2013;159:262-74

40. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy

in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise.

Diabetes Obes Metab 2013;15:372-82

41. Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin

monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet

and exercise: a 24-week, randomized, double-blind, placebo-controlled, phase III study.

Expert Opin Pharmacother 2014;15:1501-15

25


42. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52

weeks in patients with type 2 diabetes on background metformin and pioglitazone.


43. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of

canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on

background metformin monotherapy: a randomised trial. Diabetologia 2013;56:2582-92

44. Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor

of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in

patients with type 2 diabetes. Diabetes Care 2015;38:403-11

45. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in

patients with type 2 diabetes mellitus inadequately controlled with metformin and

sulphonylurea: a randomised trial. Int J Clin Pract 2013;67:1267-82

46. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus

glimepiride in patients with type 2 diabetes inadequately controlled with metformin

(CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-

inferiority trial. Lancet 2013;382:941-50

47. Langslet G, Cefalu WT, Leiter LA, et al. Canagliflozin demonstrates durable glycaemic

improvements over 104 weeks compared with glimepiride in subjects with type 2

diabetes mellitus on metformin. European Association for the Study of Diabetes (EASD);

2013 September 23-27, 2013; Barcelona, Spain. Abstract #182

48. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin

for patients with type 2 diabetes who do not have adequate glycemic control with

26


metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 2013;36:2508-

15

49. Ji L, Ma J, Li H, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with

type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther

2014;36:84-100 e9

50. Bailey CJ, Iqbal N, T'Joen C, List JF. Dapagliflozin monotherapy in drug-naive patients

with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab

2012;14:951-9

51. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic

patients with inadequate glycemic control by diet and exercise: a randomized, double-

blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24

52. Kaku K, Kiyosue A, Inoue S, et al. Efficacy and safety of dapagliflozin monotherapy in

Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.


53. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2

diabetes who have inadequate glycaemic control with metformin: a randomised, double-

blind, placebo-controlled trial. Lancet 2010;375:2223-33

54. Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with

type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern

Med 2012;156:405-15

55. Jabbour SA, Hardy E, Sugg J, et al. Dapagliflozin is effective as add-on therapy to

sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind,

placebo-controlled study. Diabetes Care 2014;37:740-50

27


56. Rosenstock J, Vico M, Wei L, et al. Effects of dapagliflozin, an SGLT2 inhibitor, on

HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes

inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012;35:1473-8

57. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2

diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-

week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38

58. Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2

diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-

controlled 102-week trial. BMC Med 2013;11:43

59. Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycaemic response and

tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in

patients with type 2 diabetes: 4-year data. Diabetes Obes Metab 2015;17:581-90

60. Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both:

initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract

2012;66:446-56

61. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy

in patients with type 2 diabetes who have inadequate glycemic control with metformin: a

randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care

2011;34:2015-22

62. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly

controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin

plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to

metformin. Diabetes Care 2015;38:376-83

28


63. Roden M, Jianping Weng J, Eilbrach J, et al. Empagliflozin monotherapy with sitagliptin

as an active comparator in patients with type 2 diabetes: a randomised, double-blind,

placebo-controlled, phase 3 trial. Lancet 2013;1:208-19

64. Ridderstrale M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and

glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week

randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol

2014;2:691-700

65. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin

in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled

trial. Diabetes Care 2014;37:1650-9

66. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight

control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with

type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab

2014;16:147-58

67. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin

plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind,

placebo-controlled trial. Diabetes Care 2013;36:3396-404

68. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as

second-line therapy in subjects with type 2 diabetes inadequately controlled on

metformin. Diabetes Care 2015;38:384-93

69. Lewin A, DeFronzo R, Patel S, et al. Initial combination of empagliflozin and linagliptin

in subjects with type 2 diabetes. Diabetes Care 2015;38:394-402

29


70. Wilding JP, Woo V, Rohwedder K, et al. Dapagliflozin in patients with type 2 diabetes

receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab

2014;16:124-36

71. Nishimura R, Tanaka Y, Koiwai K, et al. Effect of empagliflozin monotherapy on

postprandial glucose and 24-hour glucose variability in Japanese patients with type 2

diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study.

Cardiovasc Diabetol 2015;14:11

72. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive diabetes

management algorithm. Endocr Pract 2015;21:e1-e10

73. Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin maintains glycaemic control

while reducing weight and body fat mass over 2 years in patients with type 2 diabetes

mellitus inadequately controlled on metformin. Diabetes Obes Metab 2014;16:159-69

74. Majewski C, Bakris GL. Blood pressure reduction: an added benefit of sodium-glucose

cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care 2015;38:429-30

75. Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss,

lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated

multiple daily injections of insulin in obese inadequately controlled type 2 diabetes.

Diabetes Care 2014;37:1815-23

76. Matthaei S, Bowering K, Rohwedder K, et al. Dapagliflozin improves glycemic control

and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week

randomized, double-blind clinical trial. Diabetes Care 2015;38:365-72

77. Maedler K, Carr RD, Bosco D, et al. Sulfonylurea induced beta-cell apoptosis in cultured

human islets. J Clin Endocrinol Metab 2005;90:501-6

30


78. Nicolle LE, Capuano G, Fung A, Usiskin K. Urinary tract infection in randomized phase

III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad Med

2014;126:7-17

79. Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients

with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:479-84

80. Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with

diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:473-8

81. Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a

sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a

pooled analysis of clinical studies. Curr Med Res Opin 2014;30:1109-19

82. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with

dapagliflozin in type 2 diabetes. Diabetes Care 2009;32:650-7

83. Jung CH, Jang JE, Park JY. A Novel Therapeutic Agent for Type 2 Diabetes Mellitus:

SGLT2 Inhibitor. Diabetes Metab J 2014;38:261-73

84. Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for

diabetes mellitus. J Clin Endocrinol Metab 2010;95:34-42

85. U.S. Food and Drug Administration. SGLT2 Inhibitors: Drug Safety Communication -

Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary

Tract Infections. 2015. Available at:

http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalprod

ucts/ucm475553.htm [Last accessed January 6, 2016]

31

http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm475553.htm

http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm475553.htm


86. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may

result in a serious condition of too much acid in the blood. 2015. Available at:

http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm [Last accessed January 6, 2016]

87. European Medicines Agency. Review of diabetes medicines called SGLT2 inhibitors

started. 2015. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/

SGLT2_inhibitors__20/Procedure_started/WC500187926.pdf [Last accessed September

29, 2015]

88. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with

dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 2015;21:512-

7

89. Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to

ketoacidosis. J Clin Endocrinol Metab 2015;100:2849-52

90. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises

label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone

fracture risk and new information on decreased bone mineral density. 2015. Available at:

http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm [Last accessed September 29,

2015]

91. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose

cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508

92. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2

inhibitor, improves model-based indices of beta cell function in patients with type 2

diabetes. Diabetologia 2014;57:891-901

32

http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm

http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/Procedure_started/WC500187926.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/Procedure_started/WC500187926.pdf

http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm


93. Merovci A, Mari A, Solis C, et al. Dapagliflozin lowers plasma glucose concentration

and improves beta-cell function. J Clin Endocrinol Metab 2015;100:1927-32

94. Schwartz S. Do many people with type 2 diabetes really need insulin? In: Boris Draznin

M, PhD, ed. Diabetes Case Studies. 1 ed. Alexandria, VA: American Diabetes

Association 2015

95. Geerlings S, Fonseca V, Castro-Diaz D, et al. Genital and urinary tract infections in

diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract

2014;103:373-81

96. Gerich J. Pathogenesis and management of postprandial hyperglycemia: role of incretin-

based therapies. Int J Gen Med 2013;6:877-95

97. Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable,

Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care

2015;38:1638-42

98. Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a

therapeutic target. Clin J Am Soc Nephrol 2010;5:133-41

99. Scholl-Burgi S, Santer R, Ehrich JH. Long-term outcome of renal glucosuria type 0: the

original patient and his natural history. Nephrol Dial Transplant 2004;19:2394-6

100. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and

Mortality in Type 2 Diabetes. N Engl J Med 2015;

101. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of

the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-

controlled trial. Am Heart J 2013;166:217-23 e11

33


102. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular

events (DECLARE-TIMI58). 2015. Available at:

http://clinicaltrials.gov/ct2/show/NCT01730534?term=declare&rank=2 [Last accessed

March 16, 2015]

103. Gause-Nilsson I. No Increased Risk of Cardiovascular Events with Dapagliflozin in

Elderly Patients with Type 2 Diabetes Mellitus, Cardiovascular Disease, and

Hypertension [abstract]. American Diabetes Assocation; 2015 June 5-9; Boston, MA

104. Center for Drug Evaluation and Research. Summary Review. Application number

204042Orig1s000. Available at:

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000SumR.pdf

[Last accessed December 21, 2015]

34

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000SumR.pdf

http://clinicaltrials.gov/ct2/show/NCT01730534?term=declare&rank=2


Figure Captions

Figure 1. Eleven targeted pathways associated with hyperglycemia with associated therapies.

Pathways that contribute to β-cell dysfunction are shown in maroon (liver, muscle, adipose,

brain, colon/biome, and immune dysregulation/inflammation); pathways that are associated with

outcomes of β-cell dysfunction are shown in green (reduced insulin secretion, diminished

incretin effects, α-cell defect resulting in increased glucagon secretion, stomach/small intestine

increased glucose absorption via reduced amylin secretion and hyperglycemia induced

upregulation of SGLT-2 in the kidney resulting in increased glucose reabsorption). Green arrows

pointing up and down indicate increased and decreased effects/concentrations, respectively.

Drugs targeting each pathway are indicated in blue. AGI=α-glucosidase inhibitor; DPP-

4i=dipeptidyl peptidase-4 inhibitor; GLP-1RA=glucagon-like peptide-1 receptor agonist; SGLT-

2i=sodium-glucose cotransporter-2 inhibitor; TZD=thiazolidinedione. Adapted with permission

(permission pending) from Schwartz S, Epstein S, Corkey B, Grant S. The Time is Right for New

Classification System for Diabetes Mellitus: Rationale and Implications of the β-Cell Centric

Classification Schema. Diabetes Care [in press].

Figure 2. Key events underlying the progression from normal physiology to type 2 diabetes.

IFG=impaired fasting glucose; IGT=impaired glucose tolerance. Adapted with permission

(permission pending) from Ramlo-Halsted BA, Edelman SV. The natural history of type 2

diabetes. Implications for clinical practice. Primary Care 1999 Dec;26(4):771-89.

35


Table 1. Reduction in A1C and Patient Body Weight in Key Monotherapy and Combination Therapy Studies With SGLT-2 Inhibitors

Study

Monotherapy or Combination

Therapy Treatment (n)Baseline A1C, %,

Mean ± SDChange in A1C,

%Baseline Body

Weight, kgChange in Body

Weight, kg

CANAGLIFLOZIN

Inagaki 201441 Monotherapy

24 weeks

CANA 100 mg (90)

PBO (93)

7.98±0.73

8.04±0.7

−0.74

(P<0.001)

0.29

69.1±14.5

68.6±15.2

−3.8

(P<0.001)

−0.8

Stenlof 201340 Monotherapy

26 weeks

CANA 100 mg (195)

CANA 300 mg (197)

PBO (192)

8.1±1.0

8.0±1.0

8.0±1.0

−0.77

(P<0.001)

−1.03 (P<0.001)

0.14

85.8±21.4

86.9±20.5

87.6±19.5

−2.5

(P<0.001)

−3.4

(P<0.001)

−0.5

Forst 201442 Combination

MET + PIO

26 weeks

CANA 100 mg (113)

CANA 300 mg (114)

PBO/SITA 100 mg (115)b

8.0±0.9

7.9±0.9

8.0±1.0

−0.89

(P<0.001)

−1.03

(P<0.001)

−0.26

94.2±22.2

94.4±25.9

93.8±22.4

−2.6

(P<0.001)

−3.7

(P<0.001)

−0.2

Wilding 201345 Combination

MET + SU

26 weeks

CANA 100 mg (157)

CANA 300 mg (156)

PBO (156)

8.1±0.9

8.1±0.9

8.1±0.9

−0.85

(P<0.001)

−1.06

(P<0.001)

−0.13

93.8±22.6

93.5±22.0

91.2±22.6

−1.9

(P<0.001)

−2.5

(P<0.001)

−0.8

Lavalle-Gonzalez

201343

Combination CANA 100 mg (368) 7.9±0.9 −0.79 88.8±22.2 −3.3

36


+ MET

26 weeks CANA 300 mg (367)

SITA 100 mg (366)

PBO (183)

7.9±0.9

7.9±0.9

8.0±0.9

(P<0.001)

−0.94

(P<0.001)

−0.82

NA

−0.17

85.4±20.9

87.7±21.6

86.6±22.4

(P<0.001)

−3.6

(P<0.001)

−1.1

NT

−1.1

Cefalu 201346 Combination

+ MET

52 weeks

CANA 100 mg (483)

CANA 300 mg (485)

GLIM 6–8 mg (484)

7.8±0.8

7.8±0.8

7.8±0.8

−0.82

NAa

−0.93

NAa

−0.81

86.9±20.1

86.6±19.5

86.5±19.8

‒3.7

(P<0.0001)

‒4.0

(P<0.001)

0.7

Schernthaner 201348 Combination

MET + SU

52 weeks

CANA 300 mg (378)

SITA 100 mg (378)

8.1±0.9

8.1±0.9

−1.03

NAa

−0.66

NAa

87.4±23.2

89.1±23.2

‒2.3

(P<0.001)

0.1

DAPAGLIFLOZIN

Kaku 201452 Monotherapy

24 weeks

DAPA 5 mg (86)

DAPA 10 mg (88)

PBO (87)

7.5±0.72

7.46±0.61

7.5±0.63

−0.41

(P<0.0001)

−0.45

(P<0.0001)

−0.06

65.8±14.4

69.7±13.8

66.0±12.9

−2.1

(P=0.0003)

−2.2

(P=0.0001)

−0.8

Ji 201449 Monotherapy

24 weeks

DAPA 5 mg (128)

DAPA 10 mg (133)

8.14±0.74

8.28±0.95

−1.04

(P<0.0001)

−1.11

68.9±11.4

70.9±11.6

−1.6

(P<0.001)

−2.3

37


PBO (132) 8.35 ± 0.95

(P<0.0001)

−0.29 72.2 ± 13.2

(P<0.001)

−0.3

Bailey 201250 Monotherapy

24 weeks

DAPA 5 mg (68)

PBO (68)

7.90±1.03

7.80±1.12

−0.82

(P<0.0001)

0.02

85.4±19.4

90.0±18.0

−2.7

(P=0.0022)

−1.0

Ferrannini 201051 Monotherapy

24 weeks

DAPA 5 mg (64)

DAPA 10 mg (70)

PBO (75)

7.86±0.94

8.01±0.96

7.84±0.87

−0.77

(P<0.001)

−0.89

(P<0.0001)

−0.23

87.6±17.1

94.2±18.7

88.8±19.0

−2.8

NS

−3.2

NS

−2.2

Rosenstock 201562 Combination

+ MET

24 weeks

SAXA 5 mg + DAPA 10 mg

(179)

SAXA 5 mg + PBO (176)

DAPA 10 mg + PBO (179)

8.92±1.18

9.03±1.05

8.87±1.16

−1.47

−0.88

(P<0.0001b)

−1.20

P=0.0166c

87.1±18.0

88.0±18.7

86.3±18.6

−2.1

0

NT

−2.4

NT

Jabbour 201455 Combination

SITA ± MET

24 weeks

DAPA 10 mg (225)

PBO (226)

7.9±0.8

8.0±0.8

−0.5

(P<0.0001)

0.0

91.0±21.6

89.3±20.9

−2.1

(P<0.001)

−0.3


+ PIO

24 wk

DAPA 5 mg (141)

DAPA 10 mg (140)

PBO (139)

8.40±1.03

8.37±0.96

8.34±1.00

−0.82

(P=0.0007)

−0.97

(P<0.0001)

−0.42

87.8±20.7

84.8±22.2

86.4±21.3

0.1

(P<0.0001)

−0.1

(P<0.0001

1.6


INS ± up to 2

DAPA 5 mg (212) 8.62±0.89 −0.89 93.3±17.4 −1.0

38


OADs

24 weeks DAPA 10 mg (196)

PBO (197)

8.57±0.82

8.47±0.77

(P<0.001)

−0.96

(P<0.001)

−0.39

94.5±16.8

94.5±19.8

(P<0.001)

−1.6

(P<0.001)

0.4

Henry 201260

Study 1

Study 2

Initial

Combination with

MET

24 weeks

Study 1

DAPA 5 mg + MET XR

≤2000 mg (194)

DAPA 5 mg (203)

MET XR ≤2000 mg (201)

Study 2

DAPA 10 mg + MET XR

≤2000 mg (211)

DAPA 10 mg (219)

MET XR ≤2000 mg (208)

9.2±1.3

9.1±1.4

9.2±1.3

9.1±1.3

9.1±1.3

9.1±1.3

−2.05

(P<0.0001d,e)

−1.19

−1.35

−1.98

(P<0.0001d,e)

−1.45

−1.44

84.1±19.5

86.2±21.1

85.6±20.0

88.4±19.7

88.5±19.3

87.2±19.4

−2.7

(NSd)

(P<0.0001e)

−2.6

−1.3

−3.3

(NTd)

(P<0.0001e)

−2.7

−1.4

Nauck 201161 Combination

+ MET

52 weeks

DAPA ≤10 mg (406)

GLIP ≤20 mg (408)

7.69

7.74

−0.52a

−0.52

88.4±

87.6±

−3.2

(P<0.0001)

1.4

Strojek 201157 Combination

+ GLIM

24 weeks

DAPA 5 mg (145)

DAPA 10 mg (151)

PBO (146)

8.12±0.78

8.07±0.79

8.15±0.74

−0.63

(P<0.0001)

−0.82

(P<0.0001)

−0.13

81.0

80.6

80.9

−1.6

(P=0.0091)

−2.3

(P<0.0001)

−0.7

Bailey 201053 Combination DAPA 5 mg (137) 8.17±0.96 −0.70 84.7±16.3 −3.0

39


+ MET

24 weeks DAPA 10 mg (135)

PBO (137)

7.92±0.82

8.11±0.96

(P<0.0001)

−0.84

(P<0.0001)

−0.30

86.3±17.5

87.7±19.2

(P<0.0001)

−2.9

(P<0.0001)

−0.9

EMPAGLIFLOZIN

Roden 201363 Monotherapy

24 weeks

EMPA 10 mg (224)

EMPA 25 mg (224)

SITA 100 mg (223)

PBO (228)

7.87±0.88

7.86±0.85

7.85±0.79

7.91±0.78

−0.66

(P<0.0001)

−0.78

(P<0.0001)

−0.66

(P<0.0001)

0.08

78.4±18.7

77.8±18.0

79.3±20.4

78.2±19.9

−2.3

(P<0.0001)

−2.5

(P<0.0001)

0.2

(P=0.0355)

−0.3

Ridderstrale 201464 Combination

+ MET

52/104 weeks

EMPA 25 mg (769)

GLIM 1–4 mg (780)

7.92±0.81

7.92±0.86

−0.73/

−0.66

(P<0.0001 non-

inferiority/P<0.

05 superiority)

−0.66/

−0.55

82.5±19.2

83.0±19.2

−4.5f

(P<0.0001)

Haring 201465 Combination

+ MET

24 weeks

EMPA 10 mg (217)

EMPA 25 mg (214)

PBO (207)

7.94±0.79

7.86±0.87

7.90±0.88

−0.70

(P<0.001)

−0.77

(P<0.001)

−0.13

81.6±18.5

82.2±19.3

79.7±18.6

−2.1

(P<0.001)

−2.5

(P<0.001)

−0.5

Haring 201367 Combination EMPA 10 mg (226) 8.07±0.81 −0.82 77.1±18.3 −2.2

40


+ MET + SU

24 weeks EMPA 25 mg (218)

PBO (225)

8.10±0.83

8.15±0.83

(P<0.001)

−0.77

(P<0.001)

−0.17

77.5±18.8

76.2±16.9

(P<0.001)

−2.4

(P<0.001)

−0.4

Kovacs 201366 Combination

+ PIO ± MET

24 weeks

EMPA 10 mg (165)

EMPA 25 mg (168)

PBO (165)

8.07±0.89

8.06±0.82

8.16±0.92

−0.59

(P<0.001)

−0.72

(P<0.001)

−0.11

78.0±19.1

78.9±19.9

78.1±20.1

−1.6

(P<0.001)

−1.5

(P<0.001)

0.3

Lewin 201569 Initial combination

+ LINA

24 weeks

EMPA 10 mg/LINA 5 mg


EMPA 10 mg

EMPA 25 mg

LINA 5 mg

8.04±0.96

7.99±0.95

8.05±1.03

7.99±0.97

8.05±0.89

–1.24

(P<0.001)g,h

–1.08

(P<0.001)h

–0.83

–0.95

–0.67

87.3±18.4

87.9±18.2

87.8±24.0

86.7±19.7

89.5±20.1

–2.7

(P<0.001)h

–2.0

(P=0.018)h

–2.3

–2.1

–0.8

DeFronzo 201568 Combination +

LINA add-on to

MET

24 weeks



EMPA 10 mg

EMPA 25 mg

7.95±0.80

7.9±0.79

8.0±0.93

8.02±0.83

–1.08

(P<0.001)g,h

–1.19

(P<0.001)h,i

–0.66

–0.62

86.6±19.0

85.5±20.4

85.7±18.4

87.7±17.6

–2.6

(P<0.001)h

–3.0

(P<0.001)h

–2.5

–3.2

41


LINA 5 mg 8.02±0.90 –0.70 85.0±18.3 –0.7

Included randomized trials were of at least 24 weeks duration. A1C=glycated hemoglobin; CANA=canagliflozin; DAPA=dapagliflozin; EMPA=empagliflozin; GLIM=glimepiride; GLIP=glipizide; INS=insulin; LINA=linagliptin; MET=metformin; NA=not applicable; NS=not significant; NT=not tested; OAD=oral antidiabetes drug; PBO=placebo; PIO=pioglitazone; SAXA=saxagliptin; SGLT-2=sodium-glucose cotransporter-2; SITA=sitagliptin; SU=sulfonylurea; XR=extended release. aStatistically noninferior. bDifference vs SAXA 5 + PBO. cDifference vs DAPA 10 + PBO. dDAPA + MET vs DAPA. eDAPA + MET vs MET. fDifference vs GLIM. gDifference vs EMPA 10. hDifference vs LINA 5. iDifference vs EMPA 25.

42


Table 2. Adverse Events of Interest in Key Monotherapy and Combination Therapy Studies With SGLT-2 Inhibitors

StudyMonotherapy or

Combination Therapy Treatment (n)

Genital Infections, n

(%)

Urinary Tract Infections, n

(%)Hypoglycemia, n (%)

[Majora, n (%)]CANAGLIFLOZINInagaki 201441 Monotherapy

24 weeks

CANA 100 mg (90)

PBO (93)

2 (2.2)

1 (1.1)

1 (1.1)

1 (1.1)

6 (6.6) [NR]

3 (3.2) [NR]

Stenlof 201340 Monotherapy

26 weeks

CANA 100 mg (195)

CANA 300 mg (197)

PBO (192)

12 (6.2)

13 (6.6)

4 (2.1)

14 (7.2)

10 (5.1)

8 (4.2)

7 (3.6) [0]

6 (3.0) [0]

5 (2.6) [0]

Forst 201442 Combination

MET + PIO

52 weeks

CANA 100 mg (113)

CANA 300 mg (114)

PBO/SITA 100 mg (115)b

9 (8.0)

14 (12.3)

3 (2.6)

6 (5.3)

9 (7.9)

9 (7.8)

5 (4.4) [0]

7 (6.1) [0]

7 (6.1) [0]


MET + SU

52 weeks

CANA 100 mg (157)

CANA 300 mg (156)

PBO (156)

21 (13.4)

18 (11.5)

5 (3.2)

13 (8.3)

13 (8.3)

12 (7.7)

53 (33.8) [1 (0.6)]

57 (36.5) [1 (0.6)]

28 (17.9) [1 (0.6)]

Lavalle-Gonzalez

201343

Combination

+ MET

52 weeks

CANA 100 mg (368)

CANA 300 mg (367)

SITA 100 mg (366)

PBO (183)

31 (8.4)

24 (6.5)

7 (1.9)

2 (1.2)

29 (7.9)

18 (4.9)

23 (6.3)

12 (6.6)

25 (6.8) [1(0.3)]

25 (6.8) [0]

15 (4.1) [1(0.3)]

5 (2.7) [0]

Cefalu 201346 Combination

+ MET

52 weeks

CANA 100 mg (483)

CANA 300 mg (485)

GLIM 6–8 mg (482)

43 (8.9)

54 (11.1)

8 (1.7)

31 (6.0)

31 (6.0)

22 (5.0)

27 (6.0) [2 (0.4)]

24 (5.0) [3 (0.6)]

165 (34.0) [15 (3.1)]

Schernthaner 201348 Combination

MET + SU

52 weeks

CANA 300 mg (377)

SITA 100 mg (378)

45 (11.9)

8 (2.1)

26 (15.3)

7 (4.3)

163 (43.2) [15 (4.0)]

154 (40.7) [13 (3.4)]

43


DAPAGLIFLOZIN

Kaku 201452 Monotherapy

24 weeks

DAPA 5 mg (86)

DAPA 10 mg (88)

PBO (87)

1 (1.2)

2 (2.3)

1 (1.2)

0

2 (2.3)

2 (2.3)

0 [0]

2 (2.3) [0]

0 [0]

Ji 201449 Monotherapy

24 weeks

DAPA 5 mg (128)

DAPA 10 mg (133)

PBO (132)

4 (3.1)

6 (4.5)

1 (0.8)

5 (3.9)

7 (5.3)

4 (3.0)

1 (0.8) [0]

1 (0.8) [0]

2 (1.5) [0]

Bailey 201250 Monotherapy

24 weeks

DAPA 5 mg (68)

PBO (68)

2 (2.9)

2 (2.9)

2 (2.9)

1 (1.5)

1 (1.5) [0]

0 [0]

Ferrannini 201051 Monotherapy

24 weeks

DAPA 5 mg (64)

DAPA 10 mg (70)

PBO (75)

5 (7.8)

9 (12.9)

1 (1.3)

8 (12.5)

4 (5.7)

3 (4.0)

0 [0]

2 (2.9) [0]

2 (2.7) [0]


+ MET

24 weeks

SAXA 5 mg + DAPA 10 mg

(179)

SAXA 5 mg + PBO (176)

DAPA 10 mg + PBO (179)

0

1 (0.6)

10 (5.6)

1 (0.6)

9 (5.1)

7 (3.9)

2 (1.1) [0]

2 (1.1) [0]

2 (1.1) [0]

Jabbour 201455 Combination

SITA ± MET

24 weeks

DAPA 10 mg (225)

PBO (226)

9 (8.4)

1 (0.4)

11 (4.9)

9 (4.0)

6 (2.7) [1 (0.4))]

4 (1.8) [1 (0.4)


+ PIO

24 weeks

DAPA 5 mg (141)

DAPA 10 mg (140)

PBO (139)

13 (9.2)

12 (8.6)

4 (2.9)

12 (8.5)

7 (5.0)

11 (7.9)

3 (2.1) [0]

0 [0]

1 (0.7) [0]


INS ± up to 2 OADs

48 weeks

DAPA 5 mg (212)

DAPA 10 mg (196)

PBO (197)

21 (9.9)

21 (10.7)

5 (2.5)

23 (10.8)

20 (10.2)

10 (5.1)

118 (55.7) [2 (0.9)]

105 (53.6) [3 (1.5)]

102 (51.8) [2 (1.0)]

Henry 201260 Initial Combination with Study 1

44


MET

24 weeks

DAPA 5 mg + MET XR

≤2000 mg (194)

DAPA 5 mg (203)

MET XR ≤2000 mg (201)

Study 2

DAPA 10 mg + MET XR

≤2000 mg (211)

DAPA 10 mg (219)

MET XR ≤2000 mg (208)

13 (6.7)

14 (6.9)

4 (2.0)

18 (8.5)

28 (12.8)

5 (2.4)

15 (7.7)

16 (7.9)

15 (7.5)

16 (7.6)

24 (11.0)

9 (4.3)

5 (2.6) [0]

0 [0]

0 [0]

7 (3.3) [0]

2 (0.9) [0]

6 (2.9) [0]

Nauck 201161 Combination

+ MET

52 weeks

DAPA ≤10 mg (406)

GLIP ≤20 mg (408)

50 (12.3)

11 (2.7)

44 (10.8)

26 (6.4)

14 (3.4) [0]

162 (39.7) [3 (0.7)]

Strojek 201157 Combination

+ GLIM

24 weeks

DAPA 5 mg (145)

DAPA 10 mg (151)

PBO (146)

9 (6.2)

10 (6.6)

1 (0.7)

10 (6.9)

8 (5.3)

9 (6.2)

10 (6.9) [0]

12 (7.9) [0]

7 (4.8) [0]

5 (4.0) [0]

5 (4.0) [0]

4 (3.0) [0]

Bailey 201053 Combination

+ MET

24 weeks

DAPA 5 mg (137)

DAPA 10 mg (135)

PBO (137)

18 (13.0)

12 (9.0)

7 (5.0)

10 (7.0)

11 (8.0)

11 (8.0)

EMPAGLIFLOZIN

Roden 201363 Monotherapy

24 weeks

EMPA 10 mg (224)

EMPA 25 mg (224)

SITA 100 mg (223)

PBO (228)

7 (3.0)

9 (4.0)

2 (1.0)

0

15 (7.0)

12 (5.0)

11 (5.0)

12 (5.0)

1 (0.5) [0]

1 (0.5) [0]

1 (0.5) [0]

1 (0.4) [0]

Ridderstrale 201464 Combination EMPA 25 mg (765) 90 (12.0) 105 (14.0) 32 (4.0) [NR]

45


+ MET

104 weeks

GLIM 1–4 mg (780) 17 (2.0) 102 (13.0) 197 (25.0) [NR]


+ MET

24 weeks

EMPA 10 mg (217)

EMPA 25 mg (214)

PBO (207)

8 (3.7)

10 (4.7)

0

11 (5.1)

12 (5.6)

10 (4.9)

4 (1.8) [0]

3 (1.4) [0]

1 (0.5) [0]


+ MET + SU

24 weeks

EMPA 10 mg (226)

EMPA 25 mg (218)

PBO (225)

6 (2.7)

5 (2.3)

2 (0.9)

23 (10.3)

18 (8.3)

18 (8.0)

36 (16.1) [0]

25 (11.5) [0]

19 (8.4) [0]

Kovacs 201366 Combination

+ PIO ± MET

24 weeks

EMPA 10 mg (165)

EMPA 25 mg (168)

PBO (165)

14 (8.5)

6 (3.6)

4 (2.4)

28 (17.0)

20 (11.9)

27 (16.4)

2 (1.2)[ 0]

4 (2.4) [0]

3 (1.8) [0]

Lewin 201569 Initial combination +

LINA

24 weeks



EMPA 10 mg

EMPA 25 mg

LINA 5 mg

4 (2.9)

8 (5.9)

7 (5.2)

6 (4.4)

4 (3.0)

21 (15.4)

17 (12.5)

22 (16.3)

14 (10.4)

14 (10.4)

0 [0]

0 [0]

4 (3.0) [0]

1 (0.7) [0]

1 (0.7) [0]

DeFronzo 201568 Combination + LINA

add-on to MET

24 weeks



EMPA 10 mg

EMPA 25 mg

LINA 5 mg

8 (5.9)

3 (2.2)

11 (7.9)

12 (8.5)

3 (2.3)

13 (9.6)

14 (10.2)

16 (11.4)

19 (13.5)

20 (15.2)

3 (2.2) [0]

5 (3.6) [0]

2 (1.4) [0]

5 (3.5) [0]

3 (2.3) [0]

Included randomized trials were of at least 24 weeks duration. CANA=canagliflozin; DAPA=dapagliflozin; EMPA=empagliflozin; GLIM=glimepiride; GLIP=glipizide; INS=insulin; LINA=linagliptin; MET=metformin; NR=not reported; OAD=oral antidiabetes drug; PBO=placebo; PIO=pioglitazone; SGLT-2=sodium-glucose cotransporter-2; SAXA=saxagliptin; SITA=sitagliptin; SU=sulfonylurea; XR=extended release. aDefined as an event requiring assistance with or without a prespecified plasma glucose concentration. bPatients in the PBO group were switched to sitagliptin after 26 weeks of treatment.

46


Figure 1.

47


Note to Dr. Schwartz: Should we keep the alpha cell defects pathway or remove it here and in the legend? Please refer to Reviewer 2 comment 9.


Figure 2.

48


Note: Hyperglucagonemia of alpha cells will be deleted.

Documents

· Web viewThe Time is Right for New Classification System for Diabetes Mellitus: Rationale and Implications of the β-Cell Centric Classification Schema. Diabetes Care [in press]